Pharmacokinetics of buprenorphine and its metabolite norbuprenorphine in neutered male cats anesthetized with isoflurane.

OBJECTIVE: To characterize the pharmacokinetics of buprenorphine and norbuprenorphine in isoflurane-anesthetized cats. STUDY DESIGN: Prospective experimental study. ANIMALS: A group of six healthy adult male neutered cats. METHODS: Cats were anesthetized with isoflurane in oxygen. Catheters were placed in a jugular vein for blood sampling and in a medial saphenous vein for buprenorphine and lactated Ringer's solution administration. Buprenorphine hydrochloride (40 µg kg-1 over 5 minutes) was administered intravenously. Blood samples were collected before buprenorphine administration and at various times up to 12 hours after administration. Plasma buprenorphine and norbuprenorphine concentrations were measured using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the time-concentration data using nonlinear mixed effect (population) modeling. RESULTS: A five-compartment model (three compartments for buprenorphine and two compartments for norbuprenorphine) best fitted the data. Typical value (% interindividual variability) for the three buprenorphine volumes of distribution, and the metabolic clearance to norbuprenorphine, the remaining metabolic clearance and the two distribution clearances were 157 (33), 759 (34) and 1432 (43) mL kg-1, and 5.3 (33), 16.4 (11), 58.7 (27) and 6.0 (not estimated) mL minute-1 kg-1, respectively. Typical values (% interindividual variability) for the two norbuprenorphine volumes of distribution, and the norbuprenorphine metabolic and distribution clearances were 1437 (30) and 8428 (not estimated) mL kg-1 and 48.4 (68) and 235.9 (not estimated) mL minute-1 kg-1, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The pharmacokinetics of buprenorphine in isoflurane-anesthetized cats were characterized by a medium clearance.

Plasma dopamine concentrations following dopamine infusion to isoflurane-anesthetized New Zealand White rabbits.

OBJECTIVE: To determine the pharmacokinetics of dopamine following a short infusion in isoflurane-anesthetized rabbits. STUDY DESIGN: Prospective, descriptive pharmacokinetic study. ANIMALS: A group of six adult female New Zealand White rabbits weighing 4.4 ± 0.2 kg. METHODS: Rabbits were anesthetized with isoflurane in oxygen and maintained at 1.2 × minimum alveolar concentration of isoflurane (2.3% atmosphere). Dopamine (30 µg kg-1 minute-1) was infused for 10 minutes. Arterial blood was sampled prior, during and following the infusion at various intervals for 1 hour. RESULTS: A one-compartment model with baseline concentration best fitted the time-plasma dopamine concentration data. Estimated typical population value (interindividual variability) for volume of distribution and clearance were 10.3 (232%) L kg-1 and 9.9 (508%) L minute-1 kg-1, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: There was a large degree of interindividual variation in the disposition of dopamine. The large volume of distribution and high metabolic clearance rate reported for dopamine in this study likely explains the lack of clinical efficacy of dopamine in rabbits at doses up to 30 µg kg-1 minute-1.

Pharmacokinetics of ketamine following a short intravenous infusion to isoflurane-anesthetized New Zealand White rabbits (Oryctolagus cuniculus).

OBJECTIVE: To describe the pharmacokinetics of ketamine following a short intravenous (IV) infusion to isoflurane-anesthetized rabbits. STUDY DESIGN: Prospective experimental study. ANIMALS: A total of six adult healthy female New Zealand White rabbits. METHODS: Anesthesia was induced with isoflurane in oxygen. Following determination of isoflurane minimum alveolar concentration (MAC), the isoflurane concentration was reduced to 0.75 MAC and ketamine hydrochloride (5 mg kg-1) was administered IV over 5 minutes. Blood samples were collected before and at 2, 5, 6, 7, 8, 9, 13, 17, 21, 35, 65, 125, 215 and 305 minutes after initiating the ketamine infusion. Samples were processed immediately and the plasma separated and stored at -80 °C until analyzed for ketamine and norketamine concentrations using liquid chromatography-mass spectrometry. Compartment models were fitted to the concentration-time data for ketamine and for ketamine plus norketamine using nonlinear mixed-effects (population) modeling. RESULTS: A three- and five-compartment model best fitted the plasma concentration-time data for ketamine and for ketamine plus norketamine, respectively. For the ketamine only model, the volume of distribution at steady state (Vss) was 3217 mL kg-1, metabolic clearance was 88 mL minute-1 kg-1 and the terminal half-life was 59 minutes. For the model including both ketamine and norketamine, Vss were 3224 and 2073 mL kg-1, total metabolic clearance was 107 and 52 mL minute-1 kg-1 and terminal half-lives were 52 and 55 minutes for the parent drug and its metabolite, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: This study characterized the pharmacokinetics of ketamine and norketamine in isoflurane-anesthetized New Zealand White rabbits following short IV infusion. The results obtained herein will be useful to determine ketamine infusion regimens in isoflurane-anesthetized rabbits.

Hemodynamic effects of subclinical, clinical and supraclinical plasma alfaxalone concentrations in cats.

OBJECTIVE: To characterize the hemodynamic effects of subclinical, clinical and supraclinical plasma alfaxalone concentrations in cats. STUDY DESIGN: Experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were anesthetized with desflurane in oxygen for instrumentation. Catheters were placed in a medial saphenous vein for drug administration and in a carotid artery for arterial blood pressure measurement and blood collection. A thermodilution catheter was placed in the pulmonary artery via an introducer placed in a jugular vein for measurement of central venous pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, cardiac output and core body temperature, and for sampling mixed venous blood. A lead II electrocardiogram was connected. Desflurane administration was discontinued and a target-controlled infusion system was used to administer alfaxalone to reach six plasma alfaxalone concentrations ranging from 1.0 to 30.4 mg L-1, with 7.6 mg L-1 considered a clinical concentration for anesthesia. Cardiovascular measurements were recorded, and arterial and mixed-venous blood samples were collected for blood-gas analysis and plasma alfaxalone concentration measurement at each target concentration. Data were analyzed using a repeated-measures analysis of variance and Dunnett's test for comparisons to the lowest target concentration. Significance was set at p < 0.05. RESULTS: Mean ± standard deviation plasma alfaxalone concentrations were 0.73 ± 0.32, 1.42 ± 0.41, 3.44 ± 0.40, 6.56 ± 0.43, 18.88 ± 6.81 and 49.47 ± 5.50 mg L-1 for the 1, 1.9, 3.8, 7.6, 15.2, and 30.4 mg L-1 target concentrations, respectively. PaCO2 increased with increasing target plasma alfaxalone concentrations and was 69.4 ± 14.2 mmHg (9.3 ± 1.9 kPa) at the 30.4 mg L-1 target. Some cardiovascular variables were statistically significantly affected by increasing target plasma alfaxalone concentrations. CONCLUSION AND CLINICAL RELEVANCE: Within the plasma concentration range studied, alfaxalone caused hypoventilation, but the cardiovascular effects were of small clinical significance.

Pharmacokinetics of dexmedetomidine in isoflurane-anesthetized New Zealand White rabbits.

OBJECTIVE: To characterize the pharmacokinetics of dexmedetomidine when administered as a short intravenous (IV) infusion to isoflurane-anesthetized rabbits. STUDY DESIGN: Experimental study. ANIMALS: A total of six healthy adult female New Zealand White rabbits. METHODS: Rabbits were anesthetized with isoflurane in oxygen. Following determination of isoflurane minimum alveolar concentration (MAC), the anesthetic dose was reduced to 0.7 × MAC, and dexmedetomidine hydrochloride (20 µg kg-1) was infused IV over 5 minutes. Arterial blood samples were obtained immediately before and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240 and 360 minutes following termination of the infusion. Samples were transferred into tubes containing ethylenediaminetetraacetic acid and centrifuged immediately. The plasma was harvested and stored at -80 °C until analyzed. Concentrations of dexmedetomidine in plasma were determined by liquid chromatography mass spectrometry. Compartment models were fitted to the time and concentration data using nonlinear regression. RESULTS: A three-compartment model best fit the data set. Median volume of distribution at steady state and terminal half-life were 3169 mL kg-1 (range, 2182-3859 mL kg-1) and 80 minutes (range, 72-88 minutes), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The pharmacokinetics of dexmedetomidine in isoflurane-anesthetized, healthy, New Zealand White rabbits were characterized in this study. Data from this study can be used to determine dosing regimens for dexmedetomidine in isoflurane-anesthetized rabbits.

Effects of intratesticular and incisional local anesthetic administration for castration of alpacas anesthetized with intramuscular ketamine-xylazine-butorphanol.

OBJECTIVE: To determine the effects of intratesticular and incisional injection of local anesthetics on response to castration, surgical ease, and recovery in alpacas. STUDY DESIGN: Prospective, blinded, randomized, and clinical trial. ANIMALS: Intact male alpacas (n = 38). METHODS: Alpacas were anesthetized with intramuscular butorphanol, ketamine, and xylazine (BKX). Once recumbent, alpacas were instrumented with electrocardiogram, pulse oximeter, oscillometric blood pressure, and capnography. Heart rate (HR), respiratory rate (RR), and blood pressure (BP) were recorded every minute. Treatment drug (lidocaine, bupivacaine, or saline) was infiltrated along the incision and into both testicles followed by a prescrotal closed castration. Timing of major events, presence of movement during the procedure, need for additional anesthesia, and ease of surgery were recorded. Alpacas were administered postoperative oral meloxicam and assessment was made 24 hours after recovery. RESULTS: Median RR and mean BP (MBP) were lower in the lidocaine compared with the saline treated group. Median RR, HR, and MBP were significantly lower in the bupivacaine group compared with the saline group. Fewer alpacas displayed physical response to surgical stimulus with bupivacaine. No significant differences were found between groups for timing of events, need for additional anesthesia, ease of surgery, or postoperative assessment. CONCLUSION: Intratesticular local anesthetic blunts autonomic response and facilitates castration in alpacas anesthetized with BKX with minimal negative effects. Bupivacaine may have some benefit for local anesthesia during castration compared with lidocaine.

Comparison of Doppler, oscillometric, auricular and carotid arterial blood pressure measurements in isoflurane anesthetized New Zealand white rabbits.

OBJECTIVE: To assess agreement between carotid arterial pressure and auricular arterial, thoracic limb Doppler or thoracic limb oscillometric blood pressure measurements. STUDY DESIGN: Prospective experimental study. ANIMALS: Six adult New Zealand white rabbits. METHODS: Rabbits were anesthetized with isoflurane in oxygen at 1, 1.5 and 2 MAC on two separate occasions. Catheters in the auricular and the contralateral external carotid artery were connected to calibrated pressure transducers via non-compliant tubing. Inflatable cuffs of width equal to approximately 40% of the limb circumference were placed above the carpus on both thoracic limbs with a Doppler transducer placed distal to the cuff on one. Systolic (SAP) and mean (MAP) arterial blood pressure measurements were obtained at each dose, on each occasion. Agreement between measurement techniques was evaluated by repeated measures Bland Altman analysis with carotid pressure as the reference. Variation in bias over the measurement range was evaluated by regression analysis. RESULTS: Carotid MAP and SAP ranged from 20 to 65 mmHg and 37 to 103 mmHg respectively. Bias and 95% limits of agreement for auricular and oscillometric MAP were 7 (0-14) and -5 (-21-11) mmHg, respectively, and for auricular, oscillometric and Doppler SAP were 23 (8-37), -2 (-24-20) and 13 (-14-39) mmHg, respectively. Bias varied significantly over the measurement range (p < 0.001) for all three SAP techniques but not for MAP measurements. CONCLUSIONS AND CLINICAL RELEVANCE: Limits of agreement for all measurements were large but less so for MAP than SAP. Variation in bias with SAP should be considered when using these measurements clinically.

Transcutaneous monitor approximates PaCO(2) but not PaO(2) in anesthetized rabbits.

OBJECTIVE: To compare the accuracy of transcutaneous (tc) to arterial partial pressure of carbon dioxide (PaCO(2) ) and partial pressure of oxygen (PaO(2) ) in anesthetized rabbits. STUDY DESIGN: Prospective, randomized, experimental study. ANIMALS: Eight healthy adult female New Zealand white rabbits weighing 4.05± 0.30 kg. METHODS: Isoflurane anesthetized rabbits received six treatments in random order; PaCO(2) <35, 35-45, and >45 mmHg and PaO(2) < 80, 100-200, >200 mmHg. Arterial and transcutaneous measurements were taken after 15 minutes of stabilization at each condition. Linear regression, correlation and Bland-Altman analysis were performed to compare PtcCO(2) to PaCO(2) and PtcO(2) to PaO(2) . RESULTS: Over a range of measured PaCO(2) values from 21 to 67 mmHg (n=24) mean bias for PtcCO(2) was -1 mmHg and the 95% limits of agreement were -7 to 5 mmHg. The correlation between PtcCO(2) and PaCO(2) was strong with R(2) value of 0.9454. Over the entire range of measured PaO(2) values (46-508 mmHg) mean bias for PtcO(2) was -61 mmHg and the 95% limits of agreement were -226 to 104 mmHg. Correlation was poor with R(2) =0.5969. Comparing PtcO(2) to PaO(2) over a narrower range [PaO(2) < 150 mmHg (n=13)] improved the correlation, with an R(2) value of 0.8518, mean bias of -7 mmHg and 95% limits of agreement from -33 to 19 mmHg. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy anesthetized rabbits, PtcCO(2) closely approximated PaCO(2) . In contrast PtcO(2) underestimated PaO(2) , particularly at high values. The PtcCO(2) sensor may be a useful noninvasive way to assess adequacy of ventilation in anesthetized rabbits.

Thymoma removal in a cat with acquired myasthenia gravis: a case report and literature review of anesthetic techniques.

UNLABELLED: HISTORY AND PRESENTATION: A 12 year old, 4.2 kg, domestic long hair, castrated male cat was presented with regurgitation, inability to retract the claws, general weakness, cervical ventroflexion and weight loss. A thymic mass was evident on radiographs. Acetylcholine receptor antibody titer was positive for acquired myasthenia gravis (MG). Thymectomy via midline sternotomy was scheduled. ANESTHETIC MANAGEMENT: Oxymorphone and atropine were administered subcutaneously as premedication, and anesthesia was induced with etomidate and diazepam given intravenously to effect. The cat's trachea was intubated and anesthesia was maintained with isoflurane in oxygen, and continuous infusions of remifentanil and ketamine. Epidural analgesia with preservative-free morphine was administered prior to surgery. Postoperative analgesia was provided by oxymorphone subcutaneously, interpleural bupivacaine, and fentanyl infusion. Postoperative complications included airway obstruction, hypoxemia and hypercapnia. FOLLOW-UP: The cat was discharged 3 days after surgery. Discharge medications included pyridostigmine and prednisone. Nine days after surgery, the cat had a significant increase in its activity level, and medications were discontinued. Histopathologically, the mass was consistent with a thymoma. Approximately 6 weeks later the cat became weak again and pyridostigmine and prednisone administration was resumed. CONCLUSION: The perioperative management of patients with MG for transsternal thymectomy is a complex task. The increased potential for respiratory compromise requires the anesthesiologist to be familiar with the underlying disease state, and the interaction of anesthetic and non-anesthetic drugs with MG. Careful monitoring of ventilation and oxygenation is indicated postoperatively.

Hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats.

OBJECTIVE: To characterize the hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats. STUDY DESIGN: Prospective experimental study. ANIMALS: Six healthy adult female cats weighing 4.6 ± 0.8 kg. METHODS: Dexmedetomidine was administered intravenously using target-controlled infusions to maintain nine plasma concentrations between 0 and 20 ng mL(-1) in isoflurane-anesthetized cats. The isoflurane concentration was adjusted for each dexmedetomidine concentration to maintain the equivalent of 1.25 times the minimum alveolar concentration, based on a previous study. Heart rate, systemic and pulmonary arterial pressures, central venous pressure, pulmonary artery occlusion pressure, body temperature, and cardiac output were measured at each target plasma dexmedetomidine concentration. Additional variables were calculated. Arterial and mixed-venous blood samples were collected for blood gas, pH, and (on arterial blood only) electrolyte, glucose and lactate analysis. Plasma dexmedetomidine concentration was determined for each target. Pharmacodynamic models were fitted to the data. RESULTS: Heart rate, arterial pH, arterial bicarbonate concentration, mixed-venous PO(2) , mixed-venous pH, mixed-venous hemoglobin oxygen saturation, cardiac index, stroke index, and venous admixture decreased following dexmedetomidine administration. Arterial blood pressure, central venous pressure, pulmonary arterial pressure, pulmonary arterial occlusion pressure, packed cell volume, PaO(2) , PaCO(2) , arterial hemoglobin concentration, mixed-venous PCO(2) , mixed-venous hemoglobin concentration, ionized calcium concentration, glucose concentration, rate-pressure product, systemic and pulmonary vascular resistance indices, left ventricular stroke work index, arterial oxygen concentration, and oxygen extraction increased following dexmedetomidine administration. Most variables changed in a dexmedetomidine concentration-dependent manner. CONCLUSION AND CLINICAL RELEVANCE: The use of dexmedetomidine as an anesthetic adjunct is expected to produce greater negative hemodynamic effects than a higher, equipotent concentration of isoflurane alone.

Proprioceptive function is more sensitive than motor function to desflurane anesthesia.

BACKGROUND: Evaluating the effects of sub-immobilizing anesthetic doses on movement will identify target neural circuits for investigation as sites of action for anesthetic-induced immobility. METHODS: Eleven pithed Northern Leopard frogs received 0, 0.4, 0.8, and 1.2 times the 50% effective dose for production of immobility (ED(50)) of desflurane and a further 7 received 0 and 0.4 ED(50) desflurane in random order. An electric stimulus applied to the forelimb elicited a hindlimb wiping reflex that was captured on video for later analysis. Isometric tension developed in the hindlimb during the 30 s stimulus application was measured. RESULTS: Compared to 0 ED(50), 0.4 ED(50) desflurane significantly increased latency to wipe 0.8 (0.1, 4.0) to 17.3 (0.4, 30.0) s (median [min max]), distance traveled by the hindfoot 0.42 (0.09, 1.82) to 0.89 (0.16, 4.82) m, and proximity of the hindfoot to stimulus 1 (0, 5) to 7 (1, 40) mm. It did not alter hindlimb maximum velocity or isometric tension but significantly reduced total hindlimb force 7.3 (1.7, 23.6) to 3.2 (1.4, 13.8) N. s proportionate to a reduced number of movements from 12 (3, 28) to 8 (2, 14). From 0.4 to 0.8 ED(50,) motor depressant effects of desflurane became apparent with significant reductions in maximum tension from 2.0 (0.6, 5.5) to 0.8 (0.1, 1.6) N and total force from 3.2 (1.4, 13.8) to 0.9 (0.0, 2.5) N.s. CONCLUSIONS: Proprioceptive function is more sensitive to anesthetic-induced depression than motor function in frogs. This suggests that the most anesthetic-sensitive component of the spinal neural circuitry underlying movement generation in response to noxious stimulus is prior to the level of the motoneuron.

Rat dorsal horn nociceptive-specific neurons are more sensitive than wide dynamic range neurons to depression by immobilizing doses of volatile anesthetics: an effect partially reversed by the opioid receptor antagonist naloxone.

BACKGROUND: The mechanism and site of action within the spinal cord by which volatile anesthetics produce immobility are not well understood. Little work has been done directly comparing anesthetic effects on neurons with specific functional characteristics that mediate transfer of nociceptive information within the spinal cord. METHODS: Adult male rats were anesthetized and prepared for extracellular single-unit recordings from the lumbar dorsal horn. Nociceptive-specific (NS) and wide dynamic range (WDR) neurons were identified and noxious heat-evoked neuronal spike rates evaluated at 0.8 and 1.2 anesthetic minimum alveolar anesthetic concentration (MAC) halothane or isoflurane. In another group, noxious heat-evoked responses from NS neurons were evaluated at 0.8, 1.2 MAC halothane, and 1.2 MAC halothane plus IV naloxone (0.1 mg/kg). RESULTS: Increasing halothane from 0.8 to 1.2 MAC reduced the heat-evoked neuronal responses of NS neurons (n = 9) from 827 +/- 122 (mean +/- se) to 343 +/- 48 spikes/min (P < 0.05) but not WDR neurons (n = 9), 617 +/- 79 to 547 +/- 78 spikes/min. Increasing isoflurane from 0.8 to 1.2 MAC reduced the heat-evoked neuronal response of NS neurons (n = 9) from 890 +/- 339 to 188 +/- 97 spikes/min (P < 0.05) but did not alter the response of WDR neurons (n = 9) in which evoked spike rate went from 576 +/- 132 to 601 +/- 119 spikes/min. In a separate group, the response of NS neurons went from 282 +/- 60 to 74 +/- 32 spikes/min (P < 0.05) when halothane was increased from 0.8 to 1.2 MAC. IV administration of naloxone increased the heat-evoked response to 155 +/- 46 spikes/min (P < 0.05). CONCLUSIONS: NS but not WDR neurons in the lumbar dorsal horn are depressed by peri-MAC increases of halothane and isoflurane. This depression, at least with halothane, can be partially reversed by the opioid antagonist naloxone. Given that opioid receptors are not likely involved in the mechanisms by which volatile anesthetics produce immobility, this suggests that, although the neuronal depression is of substantial magnitude and occurs concurrent to the production of immobility, it may not play a major role in the production of this anesthetic end point.

Immobilizing doses of halothane, isoflurane or propofol, do not preferentially depress noxious heat-evoked responses of rat lumbar dorsal horn neurons with ascending projections.

BACKGROUND: The spinal cord is an important site where volatile anesthetics decrease sensation and produce immobility. Beyond this knowledge, our understanding of a site of anesthetic action is limited. Previous evidence suggests that dorsal horn neurons with ascending projections may be more susceptible to depression by general anesthetics than local spinal interneurons. In this study we evaluated the effects of volatile and injectable general anesthetics on lumbar dorsal horn neurons with and without ascending projections. METHODS: Thirty-seven adult male rats underwent laminectomies at C1, for placement of a stimulating electrode, and T13/L1, for extracellular recording from the spinal cord dorsal horn. Neuronal responses to heat were evaluated under two doses of halothane, isoflurane, or propofol anesthesia. RESULTS: Under both halothane and isoflurane anesthesia, increasing the dose from 0.8 to 1.2 minimum alveolar concentration (MAC) had no significant effect on heat-evoked responses in neurons that had ascending projections identified via antidromic stimulation (AD) or those without ascending projections (nAD). Heat responses in AD neurons 1 min after i.v. administration of 3 and 5 mg/kg of propofol were reduced to 60% +/- 18% (mean +/- SE) and 39% +/- 14% of control respectively. Similarly, in nAD neurons responses were reduced to 56% +/- 14% and 50% +/- 10% of control by 3 and 5 mg/kg propofol respectively. CONCLUSIONS: Our findings suggest, at peri-MAC concentrations, these general anesthetics do not preferentially depress lumbar dorsal horn neurons with ascending projections compared to those with no identifiable ascending projections.

Hexafluorobenzene acts in the spinal cord, whereas o-difluorobenzene acts in both brain and spinal cord, to produce immobility.

BACKGROUND: Previous work demonstrated that isoflurane and halothane act on the spinal cord rather than on the brain to produce immobility in the face of noxious stimulation. These anesthetics share many effects on specific receptors, and thus do not test the broad applicability of the mediation of immobility by the cord. We sought to test such an applicability by determining whether the cord mediated the immobilizing effects of two aromatic anesthetics that differ greatly in their ability to block N-methyl-d-aspartate receptors. METHODS: We investigated the actions of hexafluorobenzene (HFB) and o-difluorobenzene (ODFB) using an intact goat model that allowed selective delivery of anesthetics to the brain. Because our results suggested a significant cerebral effect of ODFB, in other goats we administered halothane 0.5% to the brain, while determining the ODFB concentration delivered to the body (the cord) required for immobility. We chose halothane because the present and previous studies found that cerebral halothane concentrations alone required for producing immobility far exceeded those required in the cord. We also applied the above techniques to another benzene-containing anesthetic, propofol. RESULTS: Prebypass minimum alveolar concentration (MAC) for HFB was 0.82% +/- 0.14% (mean +/- sd); increased to 2.04% +/- 0.8% (P < 0.01) during selective delivery to the cranial circulation; and returned to 0.79% +/- 0.28% postbypass. Corresponding values for ODFB were 0.46% +/- 0.07%, 0.63% +/- 0.12% (P < 0.05), and 0.44% +/- 0.10%. ODFB MAC was 0.32% +/- 0.17% during selective halothane delivery to brain. But when ODFB was administered to the whole body, MAC was 0.37% +/- 0.05%, (NS). Like HFB, the halothane requirement increased threefold when delivered only to the head. In four of five animals, propofol requirements increased by 240%, but in one animal propofol requirements decreased, and the overall change was not statistically significant. CONCLUSIONS: These data suggest that HFB, like halothane, produces immobility, predominantly by a spinal cord action, and that HFB differs from ODFB with respect to brain versus spinal sites of action. Nonetheless, although ODFB can produce immobility via a cerebral action, it also can do this via an independent action in the spinal cord. Thus, our results continue to support the spinal cord as the primary site at which inhaled anesthetics, and perhaps propofol, produce immobility.

Propofol's effects on nociceptive behavior and spinal c-fos expression after intraplantar formalin injection in mice with a mutation in the gamma-aminobutyric acid-type(A) receptor beta3 subunit.

We investigated whether propofol affected nociceptive behavior and fos-like immunoreactivity (FLI) in the lumbo-sacral spinal cord after intraplantar formalin injection in wild-type (WT) mice and in mutant mice harboring a point mutation of the gamma-aminobutyric acid type(A) receptor, which renders them resistant to propofol. Bolus injection of propofol (30 mg/kg IV) in WT mice reduced phase 1 formalin-evoked behavior over the initial 2-3 min but did not alter phase 2 behavior or spinal FLI (64 +/- 19 cells/section) compared with WT mice receiving intralipid vehicle plus intraplantar formalin (57 +/- 19 cells/section). Most FLI was restricted to superficial dorsal horn laminae ipsilateral to the formalin injection. WT mice receiving a 60-min propofol infusion were anesthetized throughout and did not display nociceptive behavior but had FLI (58 +/- 11 cells/section) that did not differ significantly from the other WT groups. Mutant mice receiving bolus injection of propofol (30 mg/kg) and intraplantar formalin were not anesthetized and exhibited nociceptive behavior. The total FLI in the spinal cord was 47 +/- 29 cells/section. These data indicate that although propofol produces anesthesia, it does not prevent the FLI that is associated with nociception, a finding consistent with propofol lacking analgesic properties.

Pharmacokinetics of inhaled anesthetics in green iguanas (Iguana iguana).

OBJECTIVE: To test the hypothesis that differences in anesthetic uptake and elimination in iguanas would counter the pharmacokinetic effects of blood:gas solubility and thus serve to minimize kinetic differences among inhaled agents. ANIMALS: 6 green iguanas (Iguana iguana). PROCEDURES: Iguanas were anesthetized with isoflurane, sevoflurane, or desflurane in a Latin-square design. Intervals from initial administration of an anesthetic agent to specific induction events and from cessation of administration of an anesthetic agent to specific recovery events were recorded. End-expired gas concentrations were measured during anesthetic washout. RESULTS: Significant differences were not detected for any induction or recovery events for any inhalation agent in iguanas. Washout curves best fit a 2-compartment model, but slopes for both compartments did not differ significantly among the 3 anesthetics. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in blood:gas solubility for isoflurane, sevoflurane, and desflurane did not significantly influence differences in pharmacokinetics for the inhalation agents in iguanas.

Median effective dose of isoflurane, sevoflurane, and desflurane in green iguanas.

OBJECTIVE: To determine the median effective dose (ED(50); equivalent to the minimum alveolar concentration [MAC]) of isoflurane, sevoflurane, and desflurane for anesthesia in iguanas. ANIMALS: 6 healthy adult green iguanas. PROCEDURE: In unmedicated iguanas, anesthesia was induced and maintained with each of the 3 volatile drugs administered on separate days according to a Latin square design. Iguanas were endotracheally intubated, mechanically ventilated, and instrumented for cardiovascular and respiratory measurements. During each period of anesthesia, MAC was determined in triplicate. The mean value of 2 consecutive expired anesthetic concentrations, 1 that just permitted and 1 that just prevented gross purposeful movement in response to supramaximal electrical stimulus, and that were not different by more than 15%, was deemed the MAC. RESULTS: Mean +/- SD values for the third MAC determination for isoflurane, sevoflurane, and desflurane were 1.8 +/- 0.3%, 3.1 +/- 1.0%, and 8.9 +/- 2.1% of atmospheric pressure, respectively. The MAC for all inhaled agents was, on average, 22% greater for the first measurement than for the third measurement. CONCLUSIONS AND CLINICAL RELEVANCE: Over time, MACs decreased for all 3 agents. Final MAC measurements were similar to values reported for other species. The decrease in MACs over time may be at least partly explained by limitations of anesthetic uptake and distribution imposed by the reptilian cardiorespiratory system. Hence, for a constant end-tidal anesthetic concentration in an iguana, the plane of anesthesia may deepen over time, which could contribute to increased morbidity during prolonged procedures.

Cardiovascular effects of dopamine hydrochloride and phenylephrine hydrochloride in healthy isoflurane-anesthetized New Zealand White rabbits (Oryctolagus cuniculus).

OBJECTIVE: To determine the cardiopulmonary effects of progressively increasing infusion rates of dopamine hydrochloride and phenylephrine hydrochloride in healthy adult New Zealand White rabbits anesthetized with isoflurane. ANIMALS: 6 New Zealand White rabbits. (Oryctolagus cuniculus). PROCEDURES: Each rabbit was anesthetized on 2 occasions (≥ 2 weeks apart) with isoflurane in oxygen at 1.5 times the published isoflurane minimum alveolar concentration of 2.07%. Carotid artery and pulmonary artery catheters were placed. During each anesthetic episode, each rabbit received 5 progressively increasing doses of either dopamine (5, 10, 15, 20, or 30 µg/kg/min) or phenylephrine (0.125, 0.25, 0.5, 1.0, and 2.0 µg/kg/min). Blood gas and cardiopulmonary measurements were obtained after a 20-minute equilibration period prior to administration of the first drug dose (baseline) and after each subsequent dose administration. RESULTS: Dopamine increased stroke index at the highest infusion rate of 30 µg/kg/min; however, cardiac output and mean arterial blood pressure remained unchanged from baseline values. Administration of phenylephrine at a rate of 2 µg/kg/min increased mean arterial blood pressure to 62 mm Hg from the baseline value of 45 mm Hg. This was a result of an increase in systemic vascular resistance with a concomitant decrease in heart rate and no change in cardiac output. Blood lactate concentration increased with time when rabbits received either treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Within the dose range of 5 to 30 µg/kg/min, dopamine was not an effective treatment for isoflurane-induced hypotension in rabbits and phenylephrine was only minimally effective at a dose of 2 µg/kg/min.

Effects of fentanyl on isoflurane minimum alveolar concentration in New Zealand White rabbits (Oryctolagus cuniculus).

OBJECTIVE: To determine effects of increasing plasma fentanyl concentrations on the minimum alveolar concentration (MAC) of isoflurane in rabbits. ANIMALS: 6 adult female New Zealand White rabbits (Oryctolagus cuniculus). PROCEDURES: Rabbits were anesthetized with isoflurane in oxygen; ventilation was controlled and body temperature maintained between 38.5° and 39.5°C. Fentanyl was administered IV by use of a computer-controlled infusion system to achieve 6 target plasma concentrations. Isoflurane MAC was determined in duplicate by use of the bracketing technique with a supramaximal electrical stimulus. Blood samples were collected for measurement of plasma fentanyl concentration at each MAC determination. The MAC values were analyzed with a repeated-measures ANOVA followed by Holm-Sidak pairwise comparisons. RESULTS: Mean ± SD plasma fentanyl concentrations were 0 ± 0 ng/mL (baseline), 1.2 ± 0.1 ng/mL, 2.2 ± 0.3 ng/mL, 4.4 ± 0.4 ng/mL, 9.2 ± 0.4 ng/mL, 17.5 ± 2.6 ng/mL, and 36.8 ± 2.4 ng/mL. Corresponding mean values for isoflurane MAC were 1.92 ± 0.16%, 1.80 ± 0.16%, 1.60 ± 0.23%, 1.46 ± 0.22%, 1.12 ± 0.19%, 0.89 ± 0.14%, and 0.70 ± 0.15%, respectively. Isoflurane MAC for plasma fentanyl concentrations ≥ 2.2 ng/mL differed significantly from the baseline value. In 3 rabbits, excessive spontaneous movement prevented MAC determination at the highest plasma fentanyl concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl reduced isoflurane MAC by approximately 60% in New Zealand White rabbits. Further studies will be needed to investigate the cardiorespiratory effects of isoflurane and fentanyl combinations in rabbits; however, fentanyl may prove to be a useful adjunct to inhalation anesthesia in this species.

Cardiovascular effects of equipotent doses of isoflurane alone and isoflurane plus fentanyl in New Zealand White rabbits (Oryctolagus cuniculus).

OBJECTIVE To determine effects of equipotent concentrations of fentanyl and isoflurane, compared with isoflurane alone, on cardiovascular variables in New Zealand White rabbits (Oryctolagus cuniculus). ANIMALS 6 adult female New Zealand White rabbits. PROCEDURES Rabbits were anesthetized with isoflurane, and lungs were mechanically ventilated. The minimum alveolar concentration (MAC) of isoflurane alone (baseline) and with fentanyl administered IV to achieve 3 targeted plasma concentrations was determined for each rabbit by means of an electrical stimulus. Cardiovascular variables were measured in a separate experiment at 1.3X isoflurane MAC and equipotent doses of isoflurane plus fentanyl at the same 3 targeted plasma concentrations. Blood samples were collected for measurement of blood gas variables and plasma fentanyl concentrations. Treatment effects were evaluated by repeated-measures ANOVA followed by 2-tailed paired t tests with sequentially rejective Bonferroni correction. RESULTS Mean ± SD MAC of isoflurane was 1.95 ± 0.27%. Mean measured plasma fentanyl concentrations of 4.97, 8.93, and 17.19 ng/mL reduced isoflurane MAC by 17%, 37%, and 56%, respectively. Mean measured plasma fentanyl concentrations during cardiovascular measurements were 5.49, 10.26, and 18.40 ng/mL. Compared with baseline measurements, heart rate was significantly lower at all 3 plasma fentanyl concentrations, mean arterial blood pressure and systemic vascular resistance were significantly higher at mean fentanyl concentrations of 10.26 and 18.40 ng/mL, and cardiac output was significantly higher at 18.40 ng of fentanyl/mL. CONCLUSIONS AND CLINICAL RELEVANCE Administration of fentanyl in isoflurane-anesthetized rabbits resulted in improved mean arterial blood pressure and cardiac output, compared with isoflurane alone. This balanced anesthesia technique may prove useful in the management of clinical cases in this species.